A TFEB nuclear export signal integrates amino acid supply and glucose availability

作者：Li Linxin; Friedrichsen Hans J; Andrews Sarah; Picaud Sarah; Volpon Laurent; Ngeow Kaochin; Berridge Georgina; Fischer Roman; Borden Katherine L B; Filippakopoulos Panagis; Goding Colin R^*

来源：Nature Communications, 2018, 9(1): 2685.

DOI：10.1038/s41467-018-04849-7

How cells coordinate the response to fluctuating carbon and nitrogen availability required to maintain effective homeostasis is a key issue. Amino acid limitation that inactivates mTORC1 promotes de-phosphorylation and nuclear translocation of Transcription Factor EB (TFEB), a key transcriptional regulator of lysosome biogenesis and autophagy that is deregulated in cancer and neurodegeneration. Beyond its cytoplasmic sequestration, how TFEB phosphorylation regulates its nuclear-cytoplasmic shuttling, and whether TFEB can coordinate amino acid supply with glucose availability is poorly understood. Here we show that TFEB phosphorylation on S142 primes for GSK3 beta phosphorylation on S138, and that phosphorylation of both sites but not either alone activates a previously unrecognized nuclear export signal (NES). Importantly, GSK3 beta is inactivated by AKT in response to mTORC2 signaling triggered by glucose limitation. Remarkably therefore, the TFEB NES integrates carbon (glucose) and nitrogen (amino acid) availability by controlling TFEB flux through a nuclear import-export cycle.

• 出版日期2018-7-11